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Yossi Zeliger/TPS-IL on 9 September, 2023
Breakthrough in Understanding Food Tolerance Could Lead to Allergy and Celiac Treatments
Jerusalem, 9 June, 2025 (TPS-IL) -- In a study that not only overturns long-held assumptions about how the body distinguishes food from threats but also opens the door to new treatments for food allergies, sensitivities, and autoimmune diseases like celiac, Israeli scientists have identified the specific cellular network that allows the human immune system to tolerate food.
A team of researchers at the Weizmann Institute of Science led by Dr. Ranit Kedmi revealed that a rare class of immune cells, rather than the ones previously suspected, are responsible for preventing the immune system from attacking the food a person eats. The study was recently published in the peer-reviewed Nature journal.
“When we think about food allergies, we tend to blame an overactive immune system,” Kedmi said. “But the very ability to eat without having an allergic reaction is actually an immune achievement — and one we’ve never fully understood until now.”
According to Food Allergy Research & Education, over 33 million Americans live with life-threatening food allergies, with someone sent to the emergency room every 10 seconds.
Food, like bacteria or viruses, is a foreign substance introduced into the body, yet people eat daily without triggering an immune response. That’s because of a mechanism known as food tolerance, which starts developing in the womb, continues through breastfeeding, and matures with exposure to solid foods and gut bacteria. Instead of triggering an immune response, the body’s immune cells are trained to “stand down” when they encounter food. This process prevents allergic reactions, inflammation, and autoimmune responses — conditions that occur when this system breaks down.
For years, researchers believed that food tolerance was the result of dendritic cells — the same cells that alert the immune system to invaders — instructing the immune system to stand down. But experiments in lab animals showed that even without dendritic cells, tolerance to food still occurred. This surprising result suggested that a different, unknown player was at work.
Kedmi suspected that a little-known type of immune cell called ROR-gamma-t cells, which she studied during her postdoctoral research at New York University, might be involved. ROR-gamma-t cells promote tolerance to food and beneficial bacteria. They are especially found in the gut, where the immune system constantly interacts with food and microbes.
Kedmi’s team confirmed that when ROR-gamma-t cells were disrupted in mice, the animals rapidly developed food allergies and became unable to tolerate food.
“This was the missing piece,” Kedmi said. “These rare cells are the ones actually initiating the tolerance program.”
The study went further, uncovering a coordinated network of four types of immune cells, with ROR-gamma-t cells at the top. Using genetic engineering, the researchers sequentially eliminated different cell types in mice and examined how the immune system responded to food. They found that ROR-gamma-t cells transmit signals through two additional cell types, ultimately instructing CD8 cells — typically the immune system’s “attack units” — to stand down when food is detected.
Rather than being a passive system as previously thought, food tolerance is actively maintained by a multi-cellular immune circuit. Disruption at any point in this network can result in allergic reactions.
The scientists also tested whether this tolerance could be manipulated by bacteria. They engineered bacteria to express a food-associated protein and introduced them into mice. Despite recognizing the familiar protein, the immune system attacked the bacteria — only suspending tolerance temporarily to deal with the threat before resuming normal operation.
“Now that we understand who’s responsible and how the chain of command works, we can start figuring out where it breaks down in diseases and how to fix it,” Kedmi said.
Understanding the role of ROR-gamma-t cells opens the door to targeted therapies that restore or enhance the food tolerance mechanism and also provide a clearer understanding of celiac. Moreover, knowing the cell types involved in food tolerance could lead to new biomarkers for diagnosing food allergies or intolerance.
Because food tolerance overlaps with mechanisms that keep the immune system peaceful in the gut, the research may extend to diseases like inflammatory bowel disease, Crohn’s disease and ulcerative colitis.
